Safety and immunogenicity of H5N1 vaccine

Safety and immunogenicity of H5N1 vaccine

Correspondence income have been added to the direct costs of medical care for varicella illness.4 If developed country governments are truly committe...

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Correspondence

income have been added to the direct costs of medical care for varicella illness.4 If developed country governments are truly committed to the cause of global social justice,5 they should be willing to forego the marginal benefits offered by vaccines such as the varicella vaccines and redirect these resources to ensuring that children in developing countries have greater access to an expanded range of lifesaving vaccines. I declare that I have no conflict of interest.

David N Durrheim [email protected] University of Newcastle, Private Bag 10, Wallsend, 2287 New South Wales, Australia 1 2

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Heininger U, Seward JF. Varicella. Lancet 2006; 368: 1365–76. Brisson M, Edmunds W, Gay N, Law B, De Serres G. Modelling the impact of immunisation on the epidemiology of varicella zoster virus. Epidemiol Infect 2000; 125: 651–69. Thomas SL, Wheeler JG, Hall AJ. Contacts with varicella or with children and protection against herpes zoster: a case-control study. Lancet 2002; 360: 678–82. Davis MM. Varicella vaccine, cost-effectiveness analysis and vaccination policy. JAMA 2005; 294: 845–46. Benatar SR, Daar AS, Singer PA. Global health challenges: the need for an expanded discourse on bioethics. PLoS Med 2005; 2: e143.

Payments for health care in India Eddy van Doorslaer and colleagues (Oct 14, p 1357)1 recognise the impoverishing effect of out-ofpocket (OOP) expenditure on Asian households. However, they do not explore an important element: the role of the providers, especially in the private sector, in contributing to high OOP payments. We take the example of India to highlight this issue. India has the highest number of poor in the world; it is also one of the countries with the highest proportion of OOP payments for health care. However, most of these payments are in the private sector. Peters and colleagues2 have shown that, even in poor Indian families, 79% of all

ambulatory care and 40% of all hospital admissions are in the private sector. Moreover, most of these OOP payments are made at the time of illness and the providers charge on a fee-for-service basis.3 A tremendous burden is placed on families because they have to mobilise resources when they are most vulnerable. This situation is further compounded by the poor quality of health care in the unregulated private sector4 that results in unnecessary interventions and overprescriptions. We have found that more than 10% of all women between 18 and 45 years admitted to private hospitals in rural India had a hysterectomy, usually for dubious indications such as “pelvic inflammatory disease” or “white discharge per vagina” (unpublished data). The government of India has proposed the introduction of health insurance. However, although this might protect households from direct OOP, it will still expose them to poor quality care and might even result in cost escalation.5 So risk pooling needs to be accompanied by regulation of the private sector and quality assurance mechanisms. We declare that we have no conflict of interest.

*N Devadasan, Wim Van Damme [email protected] AMCHSS, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala 695011, India (ND); and Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium (ND, WVD) 1

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van Doorslaer E, O’Donnell O, Rannan-Eliya RP, et al. Effect of payments for health care on poverty estimates in 11 countries in Asia: an analysis of household survey data. Lancet 2006; 368: 1357–61. Peters D, Yazbeck A, Sharma R, Ramana G, Pritchett L, Wagstaff A. Better health systems for India’s poor. Washington: World Bank, 2002. Bhat Ramesh. Characteristics of private medical practice in India: a provider perspective. Health Policy Planning 1999; 14: 26–37. Ranson M, John K. Quality of hysterectomy care in rural Gujarat: the role of communitybased health insurance. Reprod Health Matters 2002; 10: 70–81. Bogg L, Hengjin D, Keli W, Wenwei C, Diwan V. The cost of coverage: rural health insurance in China. Health Policy Planning 1996; 11: 238–52.

Safety and immunogenicity of H5N1 vaccine Jean-Louis Bresson and colleagues (May 20, p 1657)1 report a phase I randomised trial of an inactivated H5N1 influenza vaccine. This work provides convincing evidence for the efficacy and short-term safety of this vaccine. However, we have some concerns about the long-term safety of this adjuvant-containing formulation. The manufacturer chose aluminium hydroxide, a long-used adjuvant known to potentiate immune response through strong Th2 immunostimulatory effects.2 It was regarded as safe and devoid of any severe adverse effects, but the emergence of macrophagic myofasciitis should lead vaccinologists to revisit this view.3 Macrophagic myofasciitis is characterised by focal accumulation of aluminiumhydroxide-loaded macrophages at the site of previous intramuscular vaccination, representing unexpected long-term persistence of aluminium hydroxide after injection (median 53 months, range 3 months to 8 years).3 Macrophagic myofasciitis lesions were associated with myalgias and fatigue, most patients fulfilling diagnostic criteria for chronic fatigue syndrome.3 Thus it seems clear that aluminum hydroxide does not fulfil the need for adjuvants to be “biodegradable and easily removed from the body”4 and that the possible long-term adverse effects induced by this compound should be assessed.5 We believe that trials assessing new vaccines containing aluminium hydroxide adjuvant should include long-term follow-up of enrolled participants. We declare that we have no conflict of interest.

*F J Authier, R K Gherardi [email protected] Reference Centre for Neuromuscular Disorders, Henri Mondor Hospital, AP-HP, INSERM E0011, Faculty of Medicine, University of Paris, 12 Val de Marne, 94000 Créteil, France

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Bresson JL, Perronne C, Launay O, et al. Safety and immunogenicity of an inactivated splitvirion influenza A/Vietnam/1194/ 2004 (H5N1) vaccine: phase I randomised trial. Lancet 2006; 367: 1657–64. Brewer JM, Conacher M, Hunter CA, Mohrs M, Brombacher F, Alexander J. Aluminum hydroxide adjuvant initiates strong antigenspecific Th2 responses in the absence of IL-4 and IL-13-mediated signaling. J Immunol 1999; 163: 6448–54. Gherardi RK, Authier FJ. Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Immunol Allergy Clin N Am 2003; 23: 699–712. Clements CJ, Griffiths E. The global impact of vaccines containing aluminium adjuvants. Vaccine 2002; 20: S24–33. Del Giudice G, Podda A, Rappuoli R. What are the limits of adjuvanticity? Vaccine 2002; 20:S38–41.

Suboptimum use of FDA drug advisory committees

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18 drug advisory committees provide the US Food and Drug Administration (FDA) with independent advice. However, there have been virtually no quantitative examinations of how the committees function. We expanded on the database from our previous study on FDA advisory committees1 to cover meetings between Jan 1, 1997, and June 30, 2006. Data were collected from meeting agendas and transcripts posted on the website of the FDA’s Center for Drug Evaluation and Research.2 35 (24%) of 147 new molecular entities (NMEs) approved between 2000 and June 30, 2006, were preceded by advisory committee meetings (annual range 15–38%). This represents a decrease from 1998 and 1999 when 40% and 52%, respectively, of approved NMEs were preceded by meetings.3 NMEs with “priority” reviews (generally less than 6 months) were twice as likely to be preceded by an advisory committee meeting as NMEs approved through standard review. For the period Jan 1, 1997, to June 30, 2006, the FDA did not make an oral scientific presentation at 18% (49/275) of drug advisory committee meetings (annual range 0–33%),

but there was no trend over time. In such cases, the sponsor is allowed to make an oral presentation without a countervailing FDA presentation. Finally, we used our previous data for 2001–04 on advisory committee vote outcomes, coded as favourable or not favourable to the drug under discussion, and then used an online catalogue of FDA-approved products4 to determine what regulatory decision the FDA made on the drug in the following 12 months. Advisory committee recommendations were followed by inconsistent FDA actions 20 of 71 times. Meetings with advisory committee votes favourable to the product were not more likely to be over-ridden by the FDA than those with unfavourable outcomes. The closeness of the advisory committee vote was not a predictor of the likelihood of a subsequent inconsistent FDA action. To summarise, a declining minority of products faces advisory committees, the FDA frequently elects not to present its own interpretations of the sponsor’s data, and the rate of inconsistency between advisory committee recommendations and subsequent FDA actions is higher (28%) than is generally assumed,5 even though the follow-up period studied (1 year) is so short that few additional data could have been generated by the sponsor in the interim. On the basis of these analyses, the FDA is making suboptimum use of its drug advisory committee system. We declare that we have no conflict of interest.

Asa L Tapley, *Peter Lurie, Sidney M Wolfe [email protected] Public Citizen’s Health Research Group, 1600 20th Street, Washington, DC 20009, USA 1

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Lurie P, Almeida C, Stine N, Stine AR, Wolfe SM. Financial conflict of interest disclosure and voting patterns at food and drug administration drug advisory committee meetings. JAMA 2006; 295: 1921–28. US Food and Drug Administration: Center for Drug Evaluation and Research. http://www.fda. gov/oc/advisory/acdrugs.html (accessed June 6, 2006).

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Rehnquist J. FDA’s review process for new drug applications: a management review. Washington, DC: Office of Inspector General, Department of Health and Human Services, 2003. http://oig.hhs.gov/oei/reports/oei-01-0100590.pdf (accessed July 20, 2006). US Food and Drug Administration. [email protected] http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm (accessed June 29, 2006). Pollack A. Expected ban on primatene mist raises some concerns. New York Times May 11, 2006.

Department of Error Rolfs A, Böttcher T, Zschiesche M, et al. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 2005; 366: 1794–96—In this Article (Nov 19, 2005), the second sentence of the Acknowledgments section (p 1796) should have read: “We thank Genzyme Corporation, Germany, and TKT Germany for supporting our analytical laboratory. Neither organisation was responsible for the results of the study and did not approve it for publication.” Koblinsky M, Matthews Z, Hussein J, et al, on behalf of the Maternal Survival Series steering group. Going to scale with professional skilled care. Lancet 2006; 368: 1377–86—In this Series article (Oct 14), Bruno Marchal and Vincent De Brouwere (Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium) were omitted from the authorship list (p 1377). The authors should have been listed as: Koblinsky M, Matthews Z, Hussein J, Mavalankar D, Mridha MK, Anwar I, Achadi E, Adjei S, Padmanabhan P, Marchal B, De Brouwere V, van Lerberghe W, on behalf of The Lancet Maternal Survival Series steering group. Wim Van Lerberghe’s affiliation should have been “Department for Health Policy, Development, and Services”. The fourth bullet of panel 1 (p 1377) should have read “will increase coverage in Bangladesh by up to 40%”. The Acknowledgments section should have included “We thank Dominique Dubourg (Institute of Tropical Medicine, Antwerp, Belgium) for providing figure 2.”

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